rs145110602

Variant names:

• chrX-14844672-C-T
• rs145110602
• NM_001018113.3:c.1996G>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_001018113.3(FANCB):​c.1996G>A​(p.Gly666Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00084 in 1,208,885 control chromosomes in the GnomAD database, including 7 homozygotes. There are 276 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0032 (1 hom., 103 hem., cov: 23)
  • Exomes 𝑓: 0.00060 (6 hom. 173 hem.)
• Consequence: FANCB NM_001018113.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: 0.455
• Publications: 1 publications found

Genes affected

FANCB (HGNC:3583): (FA complementation group B) This gene encodes a member of the Fanconi anemia complementation group B. This protein is assembled into a nucleoprotein complex that is involved in the repair of DNA lesions. Mutations in this gene can cause chromosome instability and VACTERL syndrome with hydrocephalus. [provided by RefSeq, Apr 2016]

FANCB Gene-Disease associations (from GenCC):

• Fanconi anemia complementation group B

  Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: ClinGen, G2P, Labcorp Genetics (formerly Invitae)
• VACTERL association, X-linked, with or without hydrocephalus

  Inheritance: XL Classification: STRONG Submitted by: Genomics England PanelApp
• Fanconi anemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• VACTERL with hydrocephalus

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• X-linked complex neurodevelopmental disorder

  Inheritance: XL Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0074588656).
• BP6: Variant X-14844672-C-T is Benign according to our data. Variant chrX-14844672-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 246612.
• BS2: High Hemizygotes in GnomAd4 at 103 AR,XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001018113.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FANCB	NM_001018113.3	MANE Select	c.1996G>A	p.Gly666Ser	missense	Exon 9 of 10	NP_001018123.1	Q8NB91
	FANCB	NM_001410764.1		c.1996G>A	p.Gly666Ser	missense	Exon 9 of 13	NP_001397693.1	A0A8Q3WL66
	FANCB	NM_001324162.2		c.1996G>A	p.Gly666Ser	missense	Exon 9 of 10	NP_001311091.1	Q8NB91

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FANCB	ENST00000650831.1	MANE Select	c.1996G>A	p.Gly666Ser	missense	Exon 9 of 10	ENSP00000498215.1	Q8NB91
	FANCB	ENST00000324138.7	TSL:1	c.1996G>A	p.Gly666Ser	missense	Exon 8 of 9	ENSP00000326819.3	Q8NB91
	FANCB	ENST00000452869.2	TSL:1	c.1996G>A	p.Gly666Ser	missense	Exon 9 of 11	ENSP00000397849.2	C9J5X9

Frequencies

GnomAD3 genomes AF: 0.00311 AC: 347 AN: 111473 Hom.: 1 Cov.: 23

Gnomad AFR AF: 0.0102

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000476

Gnomad ASJ AF: 0.00719

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000943

Gnomad OTH AF: 0.00334

GnomAD2 exomes AF: 0.00116 AC: 212 AN: 183142 AF XY: 0.000856

Gnomad AFR exome AF: 0.0109

Gnomad AMR exome AF: 0.000255

Gnomad ASJ exome AF: 0.00601

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000159

Gnomad OTH exome AF: 0.000888

GnomAD4 exome AF: 0.000604 AC: 663 AN: 1097362 Hom.: 6 Cov.: 30 AF XY: 0.000477 AC XY: 173 AN XY: 362772

African (AFR) AF: 0.0124 AC: 327 AN: 26387

American (AMR) AF: 0.000455 AC: 16 AN: 35203

Ashkenazi Jewish (ASJ) AF: 0.00645 AC: 125 AN: 19377

East Asian (EAS) AF: 0.00 AC: 0 AN: 30194

South Asian (SAS) AF: 0.0000370 AC: 2 AN: 54119

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40531

Middle Eastern (MID) AF: 0.000725 AC: 3 AN: 4136

European-Non Finnish (NFE) AF: 0.000107 AC: 90 AN: 841358

Other (OTH) AF: 0.00217 AC: 100 AN: 46057

GnomAD4 genome AF: 0.00317 AC: 353 AN: 111523 Hom.: 1 Cov.: 23 AF XY: 0.00305 AC XY: 103 AN XY: 33785

African (AFR) AF: 0.0104 AC: 319 AN: 30687

American (AMR) AF: 0.000476 AC: 5 AN: 10512

Ashkenazi Jewish (ASJ) AF: 0.00719 AC: 19 AN: 2642

East Asian (EAS) AF: 0.00 AC: 0 AN: 3560

South Asian (SAS) AF: 0.00 AC: 0 AN: 2711

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5953

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 218

European-Non Finnish (NFE) AF: 0.0000943 AC: 5 AN: 53034

Other (OTH) AF: 0.00329 AC: 5 AN: 1518

Alfa AF: 0.00120 Hom.: 51

Bravo AF: 0.00367

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0112 AC: 43

ESP6500EA AF: 0.000149 AC: 1

ExAC AF: 0.00114 AC: 139

EpiCase AF: 0.000109

EpiControl AF: 0.000356

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	1	FANCB-related disorder (1)
-	-	1	Fanconi anemia (1)
-	-	1	Fanconi anemia complementation group B (1)
-	1	-	History of neurodevelopmental disorder (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	1.9
DANN	Benign	0.40
DEOGEN2	Benign	0.062	T
FATHMM_MKL	Benign	0.027	N
LIST_S2	Benign	0.38	T
MetaRNN	Benign	0.0075	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.85	L
PhyloP100		0.46
PrimateAI	Benign	0.20	T
PROVEAN	Benign	-0.70	N
REVEL	Benign	0.033
Sift	Benign	0.56	T
Sift4G	Benign	0.78	T
Polyphen		0.098	B
Vest4		0.16
MVP		0.21
MPC		0.10
ClinPred		0.0017	T
GERP RS		-1.1
Varity_R		0.041
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs145110602; hg19: chrX-14862794; COSMIC: COSV60759880;